Effects of diet on the outcomes of rheumatic and musculoskeletal diseases (RMDs): systematic review and meta-analyses informing the 2021 EULAR recommendations for lifestyle improvements in people with RMDs

Background A EULAR taskforce was convened to develop recommendations for lifestyle behaviours in rheumatic and musculoskeletal diseases (RMDs). In this paper, the literature on the effect of diet on the progression of RMDs is reviewed. Methods Systematic reviews and meta-analyses were performed of studies related to diet and disease outcomes in seven RMDs: osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, systemic sclerosis and gout. In the first phase, existing relevant systematic reviews and meta-analyses, published from 2013 to 2018, were identified. In the second phase, the review was expanded to include published original studies on diet in RMDs, with no restriction on publication date. Systematic reviews or original studies were included if they assessed a dietary exposure in one of the above RMDs, and reported results regarding progression of disease (eg, pain, function, joint damage). Results In total, 24 systematic reviews and 150 original articles were included. Many dietary exposures have been studied (n=83), although the majority of studies addressed people with OA and RA. Most dietary exposures were assessed by relatively few studies. Exposures that have been assessed by multiple, well conducted studies (eg, OA: vitamin D, chondroitin, glucosamine; RA: omega-3) were classified as moderate evidence of small effects on disease progression. Conclusion The current literature suggests that there is moderate evidence for a small benefit for certain dietary components. High-level evidence of clinically meaningful effect sizes from individual dietary exposures on outcomes in RMDs is missing.


ABSTRACT
Background A EULAR taskforce was convened to develop recommendations for lifestyle behaviours in rheumatic and musculoskeletal diseases (RMDs). In this paper, the literature on the effect of diet on the progression of RMDs is reviewed. Methods Systematic reviews and meta-analyses were performed of studies related to diet and disease outcomes in seven RMDs: osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, systemic sclerosis and gout. In the first phase, existing relevant systematic reviews and metaanalyses, published from 2013 to 2018, were identified. In the second phase, the review was expanded to include published original studies on diet in RMDs, with no restriction on publication date. Systematic reviews or original studies were included if they assessed a dietary exposure in one of the above RMDs, and reported results regarding progression of disease (eg, pain, function, joint damage). Results In total, 24 systematic reviews and 150 original articles were included. Many dietary exposures have been studied (n=83), although the majority of studies addressed people with OA and RA. Most dietary exposures were assessed by relatively few studies. Exposures that have been assessed by multiple, well conducted studies (eg, OA: vitamin D, chondroitin, glucosamine; RA: omega-3) were classified as moderate evidence of small effects on disease progression. Conclusion The current literature suggests that there is moderate evidence for a small benefit for certain dietary components. High-level evidence of clinically meaningful effect sizes from individual dietary exposures on outcomes in RMDs is missing.

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of the leading causes of global disability. 4 5 Some RMDs have effective pharmacological treatments that limit disease progression (eg, rheumatoid arthritis (RA) 6 ), whereas others have no effective disease modifying treatment options (eg, osteoarthritis (OA) 7 ). However, in all RMDs there is room for additional improvement in outcomes. In the general population, lifestyle modifications have been shown to improve non-RMD related outcomes. For instance, diet (ie, specific food stuffs ingested as part of daily living, and supplements or nutrients ingested to improve health) has a significant impact on the risk of chronic disease 8 and benefits to mental health. 9 However, it is unclear whether lifestyle modifications, such as changes to diet, have a beneficial impact on RMD related outcomes (including disease activity, pain, function, HR-QoL, radiographic damage, fatigue and depression).
In 2018, a EULAR Taskforce was convened to develop recommendations for lifestyle improvements in people with RMDs with regards to RMD progression (including both modifiable (eg, pain, fatigue) and irreversible (eg, joint damage) outcomes). 10 The taskforce decided to focus on six lifestyle factors: diet, exercise, weight, alcohol, smoking and paid work, and seven diseases: RA, OA, axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and gout (henceforth referred to collectively as RMDs). For each of these lifestyle factors, systematic reviews were performed, aiming to collate all relevant literature on each factor in order to formulate evidence based recommendations. This article reports the results of systematic reviews on the effect of diet on progression of RMDs.

METHODS Design
This study was performed in accordance with the EULAR standard operating procedure for EULAR endorsed recommendations 11 and is reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 12

Search strategy
The articles included in this review were identified in two steps. First, a systematic search was conducted aiming to identify published systematic reviews and meta-analyses on any of the included exposures and RMDs (listed below; online supplemental tables 1 and 2) published between 1 January 2013 and 18 Septemner 2018, using the Medline, Embase and Cochrane Library databases. Two reviewers screened the titles and abstracts (JMG, MW) and then a team of four reviewers screened the eligible full texts (JMG, MW, JRC, GC; two reviewers per full text). Only systematic reviews and meta-analyses related to diet are presented in this report.
Then a systematic review of original articles of dietary interventions for people with RMDs was conducted.
Where the research team agreed that sufficient systematic reviews and meta-analyses had been published on a given exposure in a given disease, these exposures were excluded from the systematic review of original articles (OA: vitamin E, bromelain, glucosamine, willow bark extract, chondroitin, Artemisia annua extract, green lipped muscle extract, methylsulfonylmethane, avocado/ soy bean unsaponifiables, L-carnitine, curcumin, pycnogenol, Boswellia serrata extract, Curcuma longa extract, passion fruit peel extract, collagen hydrolysate; RA: marine oils, omega-3, probiotics, vitamin D). The search strategy was developed based on a predefined PICO (PICO=participants, intervention/exposure, comparison, outcome (online supplemental table 3 for search strategy)) and implemented in the Medline, Embase and CENTRAL databases on 8 March 2019. Titles and abstracts followed by full texts were screened by two reviewers (JMG, JRC).

Inclusion and exclusion criteria
For the review to identify relevant published systematic reviews and meta-analyses, the following inclusion criteria were used: ► Systematic reviews or meta-analyses of randomised controlled trials (RCTs) or observational studies. ► Including people with an RMD (OA, RA, SLE, axSpA, PsA, SSc, gout). ► Studying the relationship between diet and outcomes (see online supplemental

Risk of bias assessment
The AMSTAR-2 tool was used to assess the risk of bias in published systematic reviews and meta-analyses. 13 Each review was graded as critically low, low, moderate or high quality. The Cochrane Risk of Bias tool was used to assess methodological quality of included RCTs, 14 rating the reporting of four criteria: randomisation procedure, allocation concealment procedure, blinding of participants and blinding of assessors. Each aspect was graded as either low risk of bias, or high/unclear risk of bias. The process was aided by a machine-learning algorithm that identifies passages and estimates a grade for each category. This has been demonstrated to speed up the quality assessment process. 15 A reviewer (JMG) checked each of the algorithm's estimates and the passages that Miscellaneous Miscellaneous Miscellaneous the algorithm was using to make these estimates, and made any changes to grades where the algorithm did not identify suitable passages. The QUIPS tool was used to assess the quality of observational studies of diet. 16 Synthesis of data Due to the heterogeneity of the studies, the findings from the included studies are presented in the form of a narrative summary, sorted by RMD and then by category of diet exposure (animal products; experimental diets; food components; fruits, vegetables and other plant-based interventions; minerals and supplements; vitamins). For each exposure, results from systematic reviews are presented first where available, followed by results from individual studies published after the reviews. Where no reviews were identified, results from individual studies are presented.
If possible, the results of RCTs were pooled using random effects meta-analysis. Standardised mean differences (SMDs) were calculated if possible for individual studies and combined in meta-analyses as this allows results measured on different instruments to be combined (SMDs in online supplemental tables). An SMD is estimated as the difference between the scores of the intervention and control group at follow-up divided by the pooled SD. 17 The means and SDs were extracted from each RCT, or effect estimates (eg, ORs, relative risk ratios, adjusted where available) from observational studies. SDs were estimated from 95% confidence intervals or standard errors when not reported. Means and SDs were estimated from medians and ranges or IQRs when only these summary statistics were presented using a published formula. 18 Overall, a SMD≥0.2 was considered a small effect, ≥0.5 as a medium sized effect, and ≥0.8 as a large effect. 19 Heterogeneity was quantified using the I 2 statistic. All statistical analyses were performed using Stata version 14 (StataCorp, College Station, TX).
The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system defines high quality evidence as evidence where further research is very unlikely to change our confidence in the estimate of effect. 20 Therefore, evidence was rated as high quality if supported by meta-analyses of at least five RCTs at lowmoderate risk of bias, reporting consistent results without important limitations. 21 GRADE defines moderate quality evidence as evidence where further research is likely to have an important impact on the confidence of the estimate of effect, or may change the estimate. 20 Evidence was rated as moderate if supported by meta-analyses of at least three RCTs or supported by a single RCT with a sample size ≥100 and at low-moderate risk of bias or multiple large observational studies. GRADE defines low quality evidence as evidence where further research is very likely to have an important influence on our confidence in the estimates, or is likely to change the estimate. 20 Evidence was rated as low if supported by multiple RCTs of small sample size or high risk of bias, or by single observational studies only. GRADE defines very low quality of evidence as evidence where the estimate of the effect is very uncertain. 20 Evidence was rated as very low if supported by single small RCTs, or non-randomised trials or single arm intervention studies. Evidence could be downgraded in the event of other potential biases (such as study limitations, inconsistency of results, imprecision, publication bias 21 or conflicts of interest).

Study selection and study characteristics
The search of systematic reviews and meta-analyses yielded 1507 abstracts, of which 16 were duplicates. Of these, 125 full manuscripts were screened, of which 103 were included (figure 1). Only 24 assessed diet and progression of RMDs, and are included in this review (other references assessed other exposures within the taskforce; eg, exercise, smoking).
The search for original studies identified 4910 abstracts. After removal of 657 duplicates, 4253 titles and abstracts were screened. Of these, 203 full manuscripts were screened, of which 150 are included in this article (figure 2).

Animal products
In total, two systematic reviews, 22 23 10 RCTs, 24-33 one single-arm intervention 34 and one prospective cohort study 35 assessed animal products in OA. One metaanalysis 22 reported moderate effects of undenatured type II collagen on pain and function (pain: SMD −0.67, 95% CI −1.01 to -0.33; function: SMD −0.55, 95% CI −0.94 to -0.17). Milk consumption was studied by one prospective cohort study, which reported a reduction in joint space narrowing as milk consumption increased. 35 One small RCT reported moderate effects on pain, function and stiffness following egg-shell membrane consumption. 30 An RCT studying Channa striatus extract (common name: striped snakehead fish) reported moderate sized effects for pain, function and stiffness. 24 One meta-analysis 23 and four RCTs studying fish oil supplements were included. The meta-analysis reported small, non-significant effects of fish oil on pain (SMD −0.16, 95% CI −0.57 to 0.24) and function (SMD 0.11, 95% CI −0.13 to 0.35) in OA. 23 One meta-analysis of one RCT 22 reported a small effect of green-lipped mussel extract on pain that was not significant (SMD −0.37, 95% CI −0.81 to 0.08). Promerim was assessed by one single-arm intervention study. 34 Pain improved after receiving promerim and exercise (online supplemental tables 5-13).

Experimental diets
One meta-analysis, 36 three RCTs 37-39 and one single arm intervention study 40 assessed experimental diets for OA. One meta-analysis compared dietary restriction plus exercise versus exercise controls, reporting small benefits in favour of pain (SMD −0.24, 95% CI −0.50 to 0.02) and function (SMD −0.34, 95% CI −0.59 to -0.08). 36 One RCT reported no difference in pain or function between RMD Open RMD Open RMD Open low and very low calorie diets. 39 A single arm intervention study reported reductions in pain, functional limitations and stiffness when following a low calorie diet, 40 and a small scale RCT reported improvements on several subscales of the SF36 from a whole-food, plant based diet in OA. 38 Another small scale RCT reported no benefit of the Mediterranean diet for physical function in people with OA 37 (online supplemental tables [14][15][16][17][18].

Food components
Two prospective cohort studies using data from the Osteoarthritis Initiative assessed the association between specific food components and OA progression. 41 42 One large prospective study reported that higher fibre intake was associated with lower odds of being in high pain trajectories. 41 The other reported that higher fat intake was associated with faster joint space narrowing progression 42 (online supplemental tables 19 and 20).

Vitamins
In total, three meta-analyses, 22 79 80 three systematic reviews, 71 81 82 eight RCTs [83][84][85][86][87][88][89][90] and three prospective cohort studies [91][92][93] were identified studying vitamin supplementation for OA. RCTs testing multi-vitamins, 88 vitamin B3 89 and vitamin B12 90 reported small nonsignificant effects on pain. One prospective cohort study reported that self-reported vitamin C supplementation was not associated with lower risk of radiographic progression. 91 One RCT compared vitamin E+C versus placebo and reported a small effect on pain after 8 weeks. 87 Three meta-analyses, 22 80 The systematic reviews reported no effect on pain, but a small effect on function. Three out of six observational studies included in a systematic review reported an inverse relationship between vitamin D and radiographic progression. 82 The latest RCT not included in the meta-analyses reported no difference in pain between high and low doses of vitamin D after participants underwent total knee replacement. 83 One metaanalysis 22 and one systematic review 71 studied vitamin E.

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Both reported no effect of vitamin E on pain (SMD 0.01, 95% CI −0.44 to 0.45) and the meta-analysis reported no effect of vitamin E on function (SMD −0.10, 95% CI −0.55 to 0.35) (online supplemental tables 54-62).

Summary
There were only relatively few studies for most dietary exposures in OA, meaning that the evidence for these exposures was graded as low or very low (table 1). For diets that had moderate evidence (fish oil, chondroitin, glucosamine, vitamin D, ASU), the effect sizes for outcomes were generally small and therefore not clinically relevant.

Rheumatoid arthritis
Animal products In total, three meta-analyses, 23 94 95 one systematic review, 96 12 RCTs 97-107 and one non-randomised trial 108 assessed products derived from animals for RA. One RCT compared collagen extracted from pigskins with placebo, reporting no significant effect on pain, function and disease activity. 99 Three meta-analyses, 23 figure 3). One meta-analysis reported a small, significant effect on function (SMD −0.26, 95% CI −0.46 to -0.06), 94 whereas another reported no effect (SMD 0.05, 95% CI −0.11 to 0.21). 23 One RCT reported an improvement in disease activity, 97 whereas another reported no effect. 98 Two RCTs studied the effect of mussel extracts, 106 107 reporting small non-significant effects on pain and function (online supplemental tables 63-67).

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an RCT comparing responders with non-responders 127 studied experimental diets in RA. Multiple RCTs and non-randomised trials studied liquid elemental diets, 109 113 115 116 hypoallergenic diets, 112 117 125 ketogenic diets 124 and vegetarian or vegan diets, 111 114 118-120 123 126 127 reporting no effect on the majority of outcomes assessed, including pain, function, joint counts, acute phase reactants, and morning stiffness. One meta-analysis, 95 one RCT 110 and two non-randomised trials 121 122 studied the Mediterranean diet for RA. The meta-analysis reported no significant effect of the Mediterranean diet on fatigue (SMD 0.37, 95% CI −0.18 to 0.93). 95 The RCT 110 reported a large effect of the diet on pain and a small effect on disease activity (online supplemental tables 68-74).
Andrographis paniculata was included in one metaanalysis, which reported no effect on fatigue. 95 One RCT 131 investigated a combination of ginger, curcumin and black pepper for RA and reported large effects on the Disease Activity Score 28 (DAS28) and its components. One single arm intervention study assessed gum arabic powder, concluding that DAS28 and its components fell after administration. 137 However, there was no control group. One non-randomised trial of Nigella sativa oil reported moderate benefits in terms of pain, disease activity, tender and swollen joints and morning stiffness 136 (online supplemental tables 75-85).

Vitamins
One meta-analysis, 155 six RCTs, 147 156-160 one nonrandomised trial 161 and two single arm studies 162 163 assessed vitamin supplementation in RA. One meta-analysis 155 reported no significant effect of vitamin D supplementation on pain (MD 2.79, 95% CI −1.87 to 7.44) and disease activity (MD −0.31, 95% CI −0.86 to 0.25). Two RCTs reported inconsistent effects on pain, function and disease activity. 156 158 Two RCTs studied vitamin B6, with one 157 reporting no significant effect on disease activity, swollen/tender joint count and acute phase reactants, and the other 159 reporting no effect on CRP. One RCT 160 assessing vitamin E reported a large effect on pain, but no effect on swollen/tender joint counts and morning stiffness. Another RCT 147 reported no effect of vitamin E on acute phase reactants (online supplemental tables [99][100][101][102][103][104].

Summary
The evidence for most dietary exposures in RA was graded as low or very low (table 2), primarily due to small numbers of studies with small sample sizes. The dietary exposures with moderate quality evidence (probiotics, vitamin D, fish oil/omega-3) showed either no effect or effect sizes that are probably not clinically significant.

Systemic lupus erythematosus
Animal products One systematic review, 164 six RCTs [165][166][167][168][169][170] and one nonrandomised trial 171 assessed fish oil/omega-3 for SLE. Two out of three studies included in the systematic review 164 reported reductions in disease activity following omega-3 intervention. The largest RCT reported no difference in disease activity between omega-3 and placebo. 167 Another RCT reported reductions in disease activity in the fish group from baseline and no reduction in the placebo group, but did not compare the two groups. 168 One other RCT 166 reported large effects on pain and function following omega-3 intervention, but no effect on fatigue. Two RCTs reported no effect of omega-3 on CRP 165 168 (online supplemental tables [105][106][107].

Experimental diets
Three systematic reviews 164 172 173 identified one RCT 174 comparing a low glycaemic diet with a low calorie diet, concluding no effect on disease activity or fatigue. An RCT 175 reported a large effect of a cholesterol lowering educational programme on QoL compared with no advice (online supplemental tables [108][109][110].

Food components
Three observational cohort studies [176][177][178] assessed the association between food components and outcomes in SLE. Two cohort studies 176 177 assessed the association RMD Open RMD Open RMD Open between consumption of various food elements and risk of active disease and atherosclerotic vascular events. High consumption of vitamin B6, fibre and vitamin C was associated with lower risk of developing active disease. None of the food components investigated were associated with reduced risk of atherosclerotic vascular events. Another cohort study 178 investigated poor nutrition in SLE, reporting that lower calorie intake was associated with more organ damage and lower percentage of protein was associated with worse mental health (online supplemental tables [111][112][113].

Fruits, vegetables and other plant based interventions
Two RCTs 179 180 studied plant based interventions for SLE. One RCT 180 reported no effect of curcumin on disease activity, and the other RCT 179 reported no effect of green tea extract on disease activity, but significant benefit in terms of fatigue (median (IQR) at 3 months, green tea:

Minerals and supplements
One RCT 169 and one non-randomised trial 181 studied mineral supplementation for SLE. The non-randomised trial 181 assessed calcium+vitamin D supplementation compared with no treatment or steroid treatment. The supplements had a large effect compared with no treatment on disease activity and a moderate effect on erythrocyte sedimentation rate, but no effect compared with steroids. Another RCT 169 assessed copper supplementation, reporting no effect on disease activity (online supplemental tables 117-119).

Vitamins
One meta-analysis, 155 one systematic review 173 and two RCTs 182 183 studied vitamins in SLE. All studies assessed vitamin D, with all studies reporting no significant effect of vitamin D on disease activity, 155 182 fatigue 173 and anti-dsDNA level 155 183 (online supplemental tables 120-122).

Summary
The evidence for fish oil/omega-3 for SLE was rated as moderate but showed no effect on outcomes (table 3). The evidence for all other studies was rated as low or very low.

Axial spondyloarthritis Food components
One systematic review 184 of 16 studies assessed various food components in axSpA. There was no association between the consumption of alpha-linoleic acid, carbohydrates, linoleic acid, long-chain omega-3 fatty acids, fibre, polyunsaturated fatty acids, protein or saturated fatty acids and disease activity or acute phase reactant levels.
There was no association between fat consumption and acute phase reactant level. (online supplemental tables 123 and 124).

Minerals and supplements
One RCT 185 assessed probiotic supplementation versus placebo, reporting no significant effect on pain, function, disease activity, tender/swollen joints and spinal mobility (online supplemental tables 125 and 126).

Summary
The evidence for dietary exposures in axSpA was rated as very low (table 4).

Minerals and supplements
One RCT 189 studied supplementation of selenium, co-enzyme Q10 and vitamin E for psoriasis with joint involvement and radiographic erosion, reporting a large effect on disease severity but no effect on psoriasis severity (online supplemental tables 129 and 130).

Summary
The evidence for marine animal oil/omega-3 for PsA was rated as moderate and showed no effect on outcomes (table 4). Other dietary exposures were rated as low evidence.

Systemic sclerosis Experimental diets
Two single arm studies 190 191 assessed medical nutrition therapy for SSc. One single arm study 190 assessed a diet and lifestyle plan, reporting improvements in patient global assessment but not in QoL. Another single arm study 191 provided supplements for vitamin and mineral deficiencies and encouraged healthy eating. There were no significant changes on any of the SF36 dimensions (online supplemental tables 131 and 132).

Vitamins
Three  studied vitamin supplementation in SSc. Two RCTs tested vitamins C and E (one also included selenium and beta-carotene) for SSc, one reporting better Rodnan Skin score at 1 month, 192 the other reporting no difference in frequency of Raynaud's attacks. 193 The final RCT 194 assessed vitamin D supplementation, reporting a large effect on Rodnan skin score at 9 months (online supplemental tables [133][134][135].

Summary
The evidence for dietary exposures in SSc was rated as low or very low (table 5).

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Gout Animal products Two systematic reviews 195 196 identified one RCT 197 which assessed enriched milk powder for gout. Pain scores were significantly lower in the intervention group, but this was judged not to be clinically significant. There was no difference between the groups in terms of function, uric acid level and gout flares (online supplemental tables 136 and 137).

Fruits, vegetables and other plant based interventions
One RCT 198 studied Chinese herbal medicine and concluded it had no significant hypouricemic effect (online supplemental tables 138 and 139).

Vitamins
One RCT 199 and one single arm study 200 assessed vitamin C supplementation for gout. The control arm was treated with allopurinol in the RCT, and demonstrated greater reductions in uric acid. The single arm study reported no changes in uric acid (online supplemental tables 140 and 141).

Summary
The evidence for dietary exposures in gout was rated as low or very low (table 5).
Studies of more than one RMD One single arm study 201 of a powdered meal replacement included people with OA and people with RA, reporting a slight improvement in the 50 foot walk test. A non-randomised trial 202 assessing linoleic acid included people with RA and people with axSpA and reported no effect on tender or swollen joint count, morning stiffness, grip strength and ESR (online supplemental tables 142 and 143).

DISCUSSION
Many studies have been published assessing diet in OA and RA, with relatively fewer studies in the other RMDs. However, the majority of exposures in all RMDs have only been assessed by a handful of studies, which were often underpowered and at moderate to high risk of bias. Typically, these studies reported low effect sizes for outcomes, although some reported large effects. This could be due to publication bias 203 or influence of commercial sponsors. When many studies have been performed (eg, chondroitin for OA 70 ) or RCTs with large sample sizes have been conducted (eg, vitamin D for OA) 84 85 the effect sizes on outcomes are small and not clinically meaningful. Therefore, based on the current evidence, there is no single dietary intervention which has substantial benefits on the outcomes of people with OA and RA. 204 While there have been far fewer research studies published for the other included RMDs, again there is no consistent evidence that any dietary exposure significantly improves outcomes in these conditions. Despite this, people with RMDs should still aim for a healthy, balanced diet given the literature demonstrating the benefits in terms of non-RMD outcomes and lack of harms. 8 9 Furthermore, the impact of a healthy diet on weight and body composition (ie, calorie balance) is likely important for determining outcomes. This was the focus of a separate review as part of this project. 205 Alongside the influence of publication bias on these results, many studies were rated as having moderate or high risk of bias (see online supplementary material). Studies often failed to report on the randomisation or allocation concealment process as well as steps taken to ensure participants and assessors were blinded to group allocation. These factors could also influence the results, potentially inflating reported effect sizes. Furthermore, there was limited reporting of adverse events. This review has a number of strengths. Its broad scope allows us to gain a global understanding of the effect of diet in RMDs. The review was conducted with rigour, with multiple assessors screening the titles, abstracts and full texts. Furthermore, appropriate quality assessment tools were utilised to assess the quality of all included studies. However, given the scope of the research question it is possible that some studies were missed in the review. This was limited as much as possible by designing and testing an extensive search strategy as well as including other published systematic reviews and meta-analyses, increasing the likelihood of including as many relevant studies as possible. Furthermore, some exposures were deemed to be sufficiently covered in previous reviews and were not included in the search of original articles. However, this may mean some articles were not included (eg, due to when they were published). Lastly, while the research team included a range of experts in rheumatology research and evidence synthesis, no specific nutritionists or dietitians were included in the authorship team.
Future research on diet in RMDs should aim for higher methodological and reporting standards. Some studies did not report data in sufficient detail for extraction and thus inclusion in this review. For example, an RCT by Kjeldsen-Kragh and colleagues from 1991 tested a vegetarian diet and fasting and reported a significant improvement in many patient reported outcomes (eg, pain, disability), but only presented data in the form of line-graphs meaning no precise data could be extracted. 206 Furthermore, studies should be sufficiently powered with long-term follow-up. Standardised definitions for different diet exposures should be formulated to allow comparison across studies, and standard outcomes assessed. Finally, research into the additive or synergistic effect of different dietary components should be researched, given the complex and interrelated nature of people's diets.
In conclusion, this broad systematic review of 174 published articles shows there is large heterogeneity in the literature on the effects of diet on RMD outcomes, both within and across RMDs. There are many published research studies on RA and OA, investigating a range of dietary exposures. For the other included RMDs, the current evidence base is limited. From the current evidence, there appears to be no single dietary factor which leads to meaningful improvements in RMD outcomes.
Funding This work was funded by the European League Against Rheumatism. JMG and SV are supported by Versus Arthritis (grant number 21755) and the NIHR Manchester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests None declared.

Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.
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